Management of Secondary Progressive Multiple Sclerosis: Prophylactic Treatment—Past, Present, and Future Aspects
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Whereas the number of treatment options in relapsing-remitting multiple sclerosis (RRMS) is growing constantly, alternatives are rare in the case of secondary-progressive multiple sclerosis (SPMS). Besides mitoxantrone in North America and Europe, interferon beta-1b and beta-1a are approved for treatment in Europe. Glucocorticosteroids, azathioprine, intravenous immunoglobulins (IVIG) and cyclophosphamide (CYC), although not approved, are commonly utilized in SPMS. Currently monoclonal antibodies (mab), and masitinib are under examination for treatment for SPMS. Hematopoietic stem cell transplantation and immunoablative stem cell transplantation are therapies with the aim of reconstitution of the immune system. This review gives information on the different therapeutics and the trials that tested them. Pathophysiological considerations are presented in view of efficacy of the therapeutics. In addition, therapeutics that showed no efficacy in trials or with unacceptable side effects are topics of this review.
KeywordsSecondary progressive multiple sclerosis Interferon beta-1b Interferon beta-1a Mitoxantrone Glucocorticosteroids Azathioprine Intravenous immunoglobulins Cyclophosphamide Masitinib Daclizumab Rituximab Linomide Treatment Prophylactic treatment Management
Conflict of Interest
Paulus S. Rommer has served as a consultant for Bayer.
Olaf Stüve has received grant support from Teva Pharmaceuticals; served as a consultant for Biogen Idec, Genzyme, Novartis, and Sanofi Aventis; had travel/accommodations expenses covered/reimbursed by Teva Pharmaceuticals; served on boards for Archives of Neurology and Therapeutic Advances in Neurological Disorders; and received fees for participation in review activities such as data monitoring boards, statistical analysis, and end point committees from Teva Pharmaceuticals.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
- 3.••Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132:1175–89. Important publication that provides fundamental insights in the pathophysiology of multiple sclerosis.PubMedCrossRefGoogle Scholar
- 7.••Kieseier BC, Stüve O. A critical appraisal of treatment decisions in multiple sclerosis--old vs new. Nat Rev Neurol. 2011;7(5):255–62. In this review, the anticipated benefits of novel therapies, including reduction in disease activity, possible prevention of disability, and improvement in quality of life, are outlined. In addition, the current acceptance of potential risks — including serious or even life-threatening adverse effects, the likelihood of which may rise with increased cumulative exposure to a particular agent — by patients with MS are reviewed.PubMedCrossRefGoogle Scholar
- 9.Greenberg BM, Balcer L, Calabresi PA, Cree B, Cross A, Frohman T, et al. interferon beta use and disability prevention in relapsing-remitting Multiple Sclerosis. Arch Neurol. 2012;1–4: doi: 10.1001/jamaneurol.2013.1017.
- 14.••Kappos L, Weinshenker B, Pozzilli C, Thompson AJ, Dahlke F, Beckmann K, et al. Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials. Neurology. 2004;63(10):1779–87. A important comparison of the two trials is presented. Differences between the trials are highlighted.PubMedCrossRefGoogle Scholar
- 19.Hartung HP, Gonsette R, König N, Kwiecinski H, Guseo A, Morrissey SP, et al. Mitoxantrone in Multiple Sclerosis Study Group (MIMS). Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomized, multicenter trial. Lancet. 2002;360(9350):2018–25. Important trial.Google Scholar
- 29.Elkhalifa A, Weiner H. Cyclophosphamide treatment of MS: current therapeutic approaches and treatment regimens. Int MS. 2010;17(1):12–8.Google Scholar
- 31.The Canadian Cooperative Multiple Sclerosis Study Group. The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive Multiple Sclerosis. Lancet. 1991;337:441.Google Scholar
- 36.Bergamaschi R, Versino M, Raiola E, Citterio A, Cosi V. High-dose methylprednisolone infusion in relapsing and in chronic progressive Multiple Sclerosis patients. One year follow-up. Acta Neurol. 1993;15(1):33–43.Google Scholar
- 37.Hohol MJ, Olek MJ, Orav EJ, Stazzone L, Hafler DA, Khoury SJ, et al. Treatment of progressive Multiple Sclerosis with pulsed cyclophosphamide/methylprednisolone: response to therapy is linked to the duration of progressive disease. Mult Scler. 1999;6(5):403–9.Google Scholar
- 48.Bonab MM, Sahraian MA, Aghsaie A, Karvigh SA, Hosseinian SM, Nikbin B, et al. Autologous mesenchymal stem cell therapy in progressive Multiple Sclerosis: an open label study. Curr Stem Cell Res Ther. 2012. [Epub ahead of print].Google Scholar
- 49.Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive Multiple Sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012;11(2):150–6. doi: 10.1016/S1474-4422(11)70305-2 [Epub Jan 10, 2012].PubMedCrossRefGoogle Scholar
- 53.Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing Multiple Sclerosis. N Engl J Med. 2006;354(9):899–910.Google Scholar
- 54.O'Connor PW, Goodman A, Willmer-Hulme AJ, Libonati MA, Metz L, Murray RS, et al. Randomized multicenter trial of natalizumab in acute MS relapses: clinical, and MRI effects. Neurology. 2004;62(11):2038–43.Google Scholar
- 55.Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, et al. B-cell depletion with rituximab in relapsing-remitting Multiple Sclerosis. N Engl J Med. 2008;358(7):676–88.Google Scholar
- 58.Hawker K, O'Connor P, Freedman MS, Calabresi PA, Antel J, Simon J, et al. Rituximab in patients with primary progressive Multiple Sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66(4):460–71.Google Scholar
- 63.van Oosten BW, Lai M, Hodgkinson S, Barkhof F, Miller DH, Moseley IF, et al. Treatment of Multiple Sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial. Neurology. 1997;49(2):351–7.PubMedCrossRefGoogle Scholar
- 65.Beutler E, Sipe JC, Romine JS, Koziol JA, McMillan R, Zyroff J. The treatment of chronic progressive Multiple Sclerosis with cladribine. Proc Natl Acad Sci USA. 1996;93(4):1716–20.Google Scholar
- 69.Lehmann D, Karussis DM, Fluresco D, Mizrachi-Koll R, Ovadia H, Shezen E, et al. Immunomodulation of autoimmunity by linomide: inhibition of antigen presentation through down regulation of macrophage activity in the model of experimental autoimmune encephalomyelitis. J Neuroimmunol. 1997;74(1–2):102–10.PubMedCrossRefGoogle Scholar
- 71.Karussis DM, Meiner Z, Lehmann D, Gomori JM, Schwarz A, Linde A, et al. Treatment of secondary progressive Multiple Sclerosis with the immunomodulator linomide: a double-blind, placebo-controlled pilot study with monthly magnetic resonance imaging evaluation. Neurology. 1996;47(2):341–6.PubMedCrossRefGoogle Scholar
- 75.Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, Rocca MA, et al. Placebo-controlled trial of oral laquinimod for Multiple Sclerosis. N Engl J Med. 2012;366(11):1000–9.Google Scholar